Brain Distribution Studies Research Articles

Preparation, physicochemical characterization, ex vivo, and in vivo evaluations of asiatic acid-loaded solid lipid nanoparticles formulated with natural waxes for nose-to-brain delivery

Asiatic acid (AA) has neuroprotective potential for prevention and treatment of Alzheimer's disease. Natural waxes with various ratios of Tween 80 and Span 80 or soybean lecithin were formulated to obtain AA-loaded solid lipid nanoparticles (AA-SLN) to improve direct nose to brain transport. Optimal AA-SLN had particle size below 200 nm with uniform size distribution and zeta potential of nearly -30 mV indicating a low risk of particle aggregation. Formulation with rice bran wax, Tween 80, and soybean lecithin (AA-RwS100) showed the highest entrapment efficiency and yield of >98 % while in vitro AA release of AA-SLN was linearly up to 48 h For ex vivo permeation, confocal laser scanning microscopy (CLSM) and histopathological studies on porcine olfactory mucosa (OM) and respiratory mucosa (RM), AA-SLN showed significantly higher permeation across OM than RM (p < 0.05) up to 6 h and AA-RwS100 also showed the highest amount of drug permeated as confirmed by CLSM results. Although AA-SLN showed non-significantly lower permeation than AA solution (AA-SOL) (p > 0.05), no epithelial and mucosal structure damages were observed in OM treated with AA-RwS100 and RM treated with all AA-SLNs indicating safety for nasal administration while AA-SOL showed significant damage to both OM and RM. In addition, in vivo brain distribution study by fluorescence imaging using Rhodamine (R6g) showed higher brain distribution after intranasal administration of R6g-loaded solid lipid nanoparticles (R6g-SLN) than R6g solution (R6g-SOL) and intravenous administration of R6g-SLN, and R6g-RwS100 also showed the highest brain accumulation at 8 h post administration.

Box-Behnken Design-Based Optimization and Evaluation of Lipid-Based Nano Drug Delivery System for Brain Targeting of Bromocriptine.

Bromocriptine (BCR) presents poor bioavailability when administered orally because of its low solubility and prolonged first-pass metabolism. This poses a significant challenge in its utilization as an effective treatment for managing Parkinson's disease (PD). The utilization of lipid nanoparticles can be a promising approach to overcome the limitations of BCR bioavailability. The aim of the research work was to develop and evaluate bromocriptine-loaded solid lipid nanoparticles (BCR-SLN) and bromocriptine-loaded nanostructured lipid carriers (BCR-NLC) employing the Box-Behnken design (BBD). BCR-SLNs and BCR-NLCs were developed using the high-pressure homogenization method. The prepared nanoparticles were characterized for particle size (PS), polydispersity index (PDI), and entrapment efficiency (EE). In vitro drug release, cytotoxicity studies, in vivo plasma pharmacokinetic, and brain distribution studies evaluated the optimized lipid nanoparticles. The optimized BCR-SLN had a PS of 219.21 ± 1.3 nm, PDI of 0.22 ± 0.02, and EE of 72.2 ± 0.5. The PS, PDI, and EE of optimized BCR-NLC formulation were found to be 182.87 ± 2.2, 0.16 ± 0.004, and 83.57 ± 1.8, respectively. The in vitro release profile of BCR-SLN and BCR-NLC showed a biphasic pattern, immediate release, and then trailed due to the sustained release. Furthermore, a pharmacokinetic study indicated that both the optimized BCR-SLN and BCR-NLC formulations improve the plasma and brain bioavailability of the drug compared to the BCR solution. Based on the research findings, it can be concluded that the BCR-loaded lipid nanoparticles could be a promising carrier by enhancing the BBB penetration of the drug and helping in the improvement of the bioavailability and therapeutic efficacy of BCR in the management of PD.

Brain-targeted nasal chrysin microemulsion for reducing oxidative stress in Parkinson's disease: Pharmacodynamic, biochemical evaluation and brain distribution studies

Chrysin, a flavone reported to treat Parkinson's, has limited oral bioavailability due to poor solubility and extensive pre-systemic metabolism. Therefore, a chrysin microemulsion (Chy-ME) was developed to improve bioavailability and brain targeting for treating Parkinson's disease via the nasal route. Chy-ME was prepared using the phase titration method and characterized for physicochemical parameters, nasociliotoxicity, and anti-Parkinson activities in a rotenone-induced experimental rat model. Chy-ME showed spherical globules with a size of 365.03 nm ± 6.8, a PDI of 0.107 ± 0.0316 and a zeta potential of −24.86 mV ± 2.286. It was non-irritant to the nasal mucosa and had in vitro and ex vivo drug release of 90.52 % and 68.67 %, respectively at 24 h. The in vivo study showed significantly improved locomotor activity and catalepsy score in the Chy-ME treated group than in oral or nasal chrysin suspension groups in rats. Chy-ME treatment showed elevated dopamine levels than the other two groups. Also, enhanced oxidative stress markers, i.e., SOD, GSH, and catalase levels, indicated the antioxidant potential of Chy-ME linked with preventing neuronal damage in Parkinson's. The maximum chrysin amount was estimated in the Chy-ME group (8.3212 ± 1.8125 μg/mL) than in oral (4.1364 ± 1.1095 μg/mL) or nasal (5.0879 ± 0.0058 μg/mL) suspension groups in the brain distribution study. In vivo studies revealed the brain-targeting potential of Chy-ME, evidenced by a substantial alleviation of Parkinson's symptoms, increased dopamine levels, improved oxidative stress markers and higher chrysin content in the brain. Therefore, nasal delivery of chrysin could overcome poor oral bioavailability and be explored for treating Parkinson-related symptoms as a brain-targeted approach.

Collation of fullerenes and carbon nanotubes with genistein for synergistic anti-Alzheimer's activity by amyloid-β deaggregation

This research study aimed to compare the therapeutic potential of two pharmacologically-active carbon-based nanocarriers, Fullerene (C60) and Multi-wall carbon nanotubes (MWCNTs), both loaded with genistein (GEN), for their synergistic action on amyloid-β (Aβ) plaques in Alzheimer's disease. Utilizing a 32 Factorial design with Design Expert® software, the researchers optimized the formulations. The optimized batch OPC60 and OP-MWCNT displayed particle sizes of 444.02 ± 1.23 nm and 236.91 ± 1.22 nm, respectively, with excellent encapsulation efficiencies of 86.13 ± 2.68 % and 85.13 ± 2.89 %. Both formulations exhibited favourable in-vitro release profiles in brain pH (7.2), with OPC60 and OP-MWCNTs releasing 83.25 ± 0.36 % and 87.38 ± 0.49 %, respectively. Ex-vivo and in-vivo brain distribution studies on male Wistar rats demonstrated successful controlled release of GEN in the brain through intranasal administration. The formulations permeated the nasal membrane mainly via receptor-mediated endocytosis, involving scavenger receptor class B type 1 (SR-B1). Pharmacokinetic analysis yielded parameters for OPC60, including AUC0-24 of 6688 μgh/L, Cmax of 321 ± 4.67 μg, Tmax of 24 h, and T1/2 of 6.7 h. For OP-MWCNTs, the parameters were AUC0-24 of 5942 μgh/L, Cmax of 339.41 ± 2.84 μg, Tmax of 24 h, and T1/2 of 9.4 h. Both formulations showed promising potential for reversing Alzheimer's disease and could serve as viable alternatives soon. Further research is warranted to understand the mechanisms underlying their therapeutic effects and address safety and clinical translation challenges for large-scale production and medical applications.

Investigation into the impact of proton pump inhibitors on sertraline transport across the blood-brain barrier

As a widely used antidepressant that works by inhibiting the reuptake of serotonin, sertraline exerts an antidepressant effect depending on its concentration in the brain, which might be limited by the blood-brain barrier (BBB). It is highly possible to combine proton pump inhibitors (PPIs) with sertraline in clinical trials. Nevertheless, the role played by PPIs in regulating the transport of sertraline across the BBB remains unclear. Here, the impact of PPIs on the distribution of sertraline in the brain and the mechanisms involved were investigated. A mouse brain distribution study showed that Omeprazole (OME), Pantoprazole (PAN), Ilaprazole (ILA), and Esomeprazole (ESO) increased the area under the brain concentration-time curves (AUC) for sertraline by 2.02-, 3.18-, 3.04-, and 4.21-fold, respectively, after the 14-day administration of PPIs. Besides, PPIs significantly increased the permeability of sertraline in brain perfusion experiments, with PAN having the highest rank order, followed by ILA, OME, and ESO. In the tail suspension test (TST), co-administration PPI groups showed significantly shorter immobility time than the control group. In vitro, four PPIs inhibited sertraline efflux in breast cancer resistance protein (BCRP)-overexpressing MDCKII cells, and showed a mixed inhibition type. In this study, PPIs were further found to inhibit the mRNA and protein expression of brain BCRP. To sum up, the findings of this study revealed that PPIs could enhance the brain distribution and antidepressant effect of sertraline, which may be attributed to the inhibition of BCRP expression at the BBB by PPIs.

In vivo brain distribution study of dexamethasone encapsulated in polymeric and albumin-based nanocarriers

In vivo brain distribution study of dexamethasone encapsulated in polymeric and albumin-based nanocarriers

Intranasal spray of cubosomal tizanidine hydrochloride for brain targeting: in vitro and in vivo characterisation

Tizanidine HCl (TH) is used as first-line therapy for the treatment of muscular spasm. The intranasal cubosomal delivery system of TH for site-specific delivery, i.e. CNS was developed. Cubosomes of TH were prepared using glyceryl monooleate (GMO) as a lipid, poloxamer 407 as stabiliser, and ethanol and polyethylene glycol 200 as co-solvent. Optimised cubosomes of TH were characterised for vesicle size, zeta potential, % drug entrapment, and mucin binding efficiency, which were found to be 50.22 nm, −6.39 mV, 69.28%, and 42.12%. It is also evaluated for CRYO-FESEM, CRYO-TEM, SAXS, residual solvent content, and in vitro drug release. Ex vivo permeation was also conducted at 7.4 and it indicates that almost 93.66% drug was diffused from a formulation in 6 h. Histopathological study of the optimised TH cubosomes suggests that the prepared formulation is non-toxic to the nasal mucosa. Pharmacokinetic and brain distribution study indicates targeted action of the formulated TH cubosomes.

Novel LC-MS/MS analysis of the GLP-1 analog semaglutide with its application to pharmacokinetics and brain distribution studies in rats

Semaglutide, one of the most potent glucagon-like peptide (GLP)-1 analogs, has widely been used to treat type II diabetes mellitus and obesity. Recent studies have shown that semaglutide also works on the brain, suggesting its potential utility for various diseases, including Parkinson’s disease and Alzheimer’s disease. This study aimed to develop a novel liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis of semaglutide in both plasma and brain to characterize the pharmacokinetics and brain distribution in rats. Semaglutide was extracted by simple protein precipitation with methanol from plasma and by solid phase extraction from brain tissue. Liraglutide was used as an internal standard. Gradient elution profiles with mobile phases comprising 0.1 % formic acid in water and acetonitrile were used for chromatographic separation. The lower limit of quantification (LLOQ) of the LC-MS/MS assay was 0.5 ng/mL for both rat plasma and brain. Intra- and inter-day accuracy ranged 89.20–109.50 % in the plasma and 92.00–105.00 % in the brain. Precision was within 8.92 % in the plasma and 7.94 % in the brain. Sprague-Dawley rats were given semaglutide by intravenous (IV, 0.02 mg/kg) and subcutaneous (SC, 0.1 and 0.2 mg/kg) injection. Plasma concentrations of semaglutide showed a multi-exponential decline with an average half-life of 7.22–9.26 hr in rats. The subcutaneous bioavailability of semaglutide was 76.65–82.85 %. The brain tissue to plasma partition coefficient (Kp) value of semaglutide was estimated as <0.01. Among the different regions of the brain, semaglutide concentrations were significantly higher in the hypothalamus. The analytical method and pharmacokinetic information may be helpful toward a better understanding of the effect of semaglutide in the brain and further development of GLP-1 analogs for various brain diseases.

Spanlastics as a Potential Approach for Enhancing the Nose-To-Brain Delivery of Piperine: In Vitro Prospect and In Vivo Therapeutic Efficacy for the Management of Epilepsy

The present study delineates the preparation of piperine-loaded spanlastics (PIP-SPL) to improve piperine (PIP) solubility, bioavailability, and permeation through nasal mucosa for intranasal delivery. PIP-SPL was formulated using the thin-film hydration method and optimization was performed using Box-Behnken design (BBD). PIP-SPL optimized formulation (PIP-SPLopt) was characterized for polydispersity index (PDI), vesicle size, entrapment efficiency, zeta potential, and in vitro PIP release. For further evaluation, blood-brain distribution study, transmission electron microscopy (TEM), nasal permeation study, and confocal scanning laser microscopy (CLSM) were performed withal. The PIP-SPLopt presented spherical and sealed shape vesicles with a small vesicle size of 152.4 nm, entrapment efficiency of 72.93%, PDI of 0.1118, and in vitro release of 82.32%. The CLSM study unveiled that the developed formulation has greater permeation of PIP across the nasal mucosa in comparison with the PIP suspension. The blood-brain distribution study demonstrated higher Cmax and AUC0-24h of PIP-SPL via the intranasal route in comparison to PIP-SPL via oral administration. The in vivo study revealed that the PIP-SPL has good antiepileptic potential in comparison with the standard diazepam, which was evinced by seizure activity, neuromuscular coordination by rotarod test, biochemical estimation of oxidative stress markers, and histopathological studies. Furthermore, nasal toxicity study confirm that the developed PIP-SPL formulation is safer for intranasal application. The current investigation corroborated that the prepared spanlastic vesicle formulation is a treasured carrier for the PIP intranasal delivery for the management of epilepsy.

Anti-amyloidogenic amphipathic arginine-dehydrophenylalanine spheres capped selenium nanoparticles as potent therapeutic moieties for Alzheimer's disease.

Aggregation of both amyloid beta (Aβ) peptide and hyperphosphorylated tau proteins is the major pathological hallmark of Alzheimer's disease (AD). Moieties that carry anti-amyloidogenic potency against both of the aggregating entities are considered to be promising drug candidatures for the disease. In the current work, we have synthesized amphipathic dipeptide vesicle-templated selenium nanoparticles (RΔF-SeNPs) as potential entities to combat AD. We have investigated and established their anti-amyloidogenic activity against different peptide-based amyloid models, such as the reductionist model based on the dipeptide phenylalanine-phenylalanine (FF) derived from Aβ; a model based on the hexapeptide Ac-PHF6 (306VQIVYK311) derived from tau protein; and the full-length Aβ42 polypeptide-based model. We also evaluated the neuroprotective characteristics of RΔF-SeNPs against FF, Ac-PHF6, and Aβ42 fibril-induced toxicity in neuroblastoma, SH-SY5Y cells. RΔF-SeNPs further exhibited neuroprotective effects in streptozotocin (STZ) treated neuronal (N2a) cells carrying AD-like features. In addition, studies conducted in an intra-cerebroventricular STZ-instigated rat model of dementia revealed that RΔF-SeNP-treated animals showed improved cognitive activity and reduced Aβ42 aggregate burden in brain tissues as compared with the STZ-treated group. Moreover, in vivo brain distribution studies conducted in animal models additionally demonstrated the brain-homing ability of RΔF-SeNPs. All together, these studies supported the potency of RΔF-SeNPs as efficient and propitious disease-modifying therapeutic agents for combating AD.

Crafting ɣ-L-Glutamyl-l-Cysteine layered Human Serum Albumin-nanoconstructs for brain targeted delivery of ropinirole to attenuate cerebral ischemia/reperfusion injury via “3A approach”

Treatment of Ischemic Stroke is inordinately challenging due to its complex aetiology and constraints in shuttling therapeutics across blood-brain barrier. Ropinirole hydrochloride (Rp), a propitious neuroprotectant with anti-oxidant, anti-inflammatory, and anti-apoptotic properties (3A) is repurposed for remedying ischemic stroke and reperfusion (I/R) injury. The drug's low bioavailability in brain however, limits its therapeutic efficacy. The current research work has reported sub-100 nm gamma-L-Glutamyl-L-Cysteine coated Human Serum Albumin nanoparticles encapsulating Rp (C-Rp-NPs) for active targeting in ischemic brain to encourage in situ activity and reduce unwanted toxicities. Confocal microscopy and brain distribution studies confirmed the enhanced targeting potentiality of optimized C-Rp-NPs. The pharmacokinetics elucidated that C-Rp-NPs could extend Rp retention in systemic circulation and escalate bioavailability compared with free Rp solution (Rp-S). Additionally, therapeutic assessment in transient middle cerebral occlusion (tMCAO) model suggested that C-Rp-NPs attenuated the progression of I/R injury with boosted therapeutic index at 1000 times less concentration compared to Rp-S via reinstating neurological and behavioral deficits, while reducing ischemic neuronal damage. Moreover, C-Rp-NPs blocked mitochondrial permeability transition pore (mtPTP), disrupted apoptotic mechanisms, curbed oxidative stress and neuroinflammation, and elevated dopamine levels post tMCAO. Thus, our work throws light on fabrication of rationally designed C-Rp-NPs with enormous clinical potential.

Optimized self-microemulsifying drug delivery system improves the oral bioavailability and brain delivery of coenzyme Q10

Our study aimed to develop a self-microemulsifying drug delivery system for the poorly aqueous-soluble drug Coenzyme Q10, to improve the dissolution and the oral bioavailability. Excipients were selected based on their Coenzyme Q10 solubility, and their concentrations were set for the optimization of the microemulsion by using a D-optimal mixture design to achieve a minimum droplet size and a maximum solubility of Coenzyme Q10 within 15 min. The optimized formulation was composed of an oil (omega-3; 38.55%), a co-surfactant (Lauroglycol® 90; 31.42%), and a surfactant (Gelucire® 44/14; 30%) and exhibited a mean droplet size of 237.6 ± 5.8 nm and a drug solubilization (at 15 min) of 16 ± 2.48%. The drug dissolution of the optimized formulation conducted over 8 h in phosphate buffer medium (pH 6.8) was significantly higher when compared to that of the Coenzyme Q10 suspension. A pharmacokinetic study in rats revealed a 4.5-fold and a 4.1-fold increase in the area under curve and the peak plasma concentration values generated by the optimized formulation respectively, as compared to the Coenzyme Q10 suspension. A Coenzyme Q10 brain distribution study revealed a higher Coenzyme Q10 distribution in the brains of rats treated with the optimized formulation than the Coenzyme Q10 suspension. Coenzyme Q10-loaded self microemulsifying drug delivery system was successfully formulated and optimized by a response surface methodology based on a D-optimal mixture design and could be used as a delivery vehicle for the enhancement of the oral bioavailability and brain distribution of poorly soluble drugs such as Coenzyme Q10.

Design and synthesis of aryl-piperidine derivatives as potent and selective PET tracers for cholesterol 24-hydroxylase (CH24H)

Cholesterol 24-hydroxylase (CH24H, CYP46A1) is a cytochrome P450 family enzyme that maintains the homeostasis of brain cholesterol. Soticlestat, a potent and selective CH24H inhibitor, is in development as a therapeutic agent for Dravet syndrome and Lennox-Gastaut syndrome. Herein, we report the discovery of aryl-piperidine derivatives as potent and selective CH24H positron emission tomography (PET) tracers which can be used for dose guidance of a clinical CH24H inhibitor and as a diagnostic tool for CH24H-related pathology. Starting from compound 1 (IC50 = 16 nM, logD = 1.7), which was reported as a CH24H inhibitor with lower lipophilicity, a18F-labeling site (3-fluoroazetidine) was incorporated by structure-based drug design (SBDD) utilizing the co-crystal structure of a compound 1 analog. Subsequent optimization to adjust key parameters for PET tracers, such as potency, lipophilicity, brain penetration, and unbound plasma protein binding, enabled compounds 3f (IC50 = 8.8 nM) and 3g (IC50 = 8.7 nM) as PET imaging candidates. Selectivity of these compounds for CH24H was validated by a brain distribution study using CH24H-WT and KO mice. In non-human primate PET imaging, [18F]3f and [18F]3g showed similar regional uptake in the brain, indicating that these tracers were specific to the CH24H-expressed regions and validated the expression of CH24H in the living brain by different tracers.

Pharmacokinetic and brain distribution study of an anti-glioblastoma agent in mice by HPLC-MS/MS.

Previously compound I showed great anti-glioblastoma activity without toxicity in a mouse xenograft study. In this study, a sensitive and rapid high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) method was developed and validated to investigate the pharmacokinetics and brain distribution of compound I in mice. The protein precipitation method was applied to extract the compound from mouse plasma and brain homogenates, and it was then separated using a Kinetex C18 column with a mobile phase consisting of acetonitrile-0.1% formic acid water (50:50, v/v). The analytes were detected with multiple reaction monitoring for the quantitative response of the compounds. The inter- and intra-day precisions were <8.29 and 3.85%, respectively, and the accuracy range was within ±7.33%. The method was successfully applied to evaluate the pharmacokinetics of compound I in mouse plasma and brain tissue. The peak concentration in plasma was achieved within 1h. The apparent elimination half-life was 4.06 h. The peak concentration of compound I in brain tissue was 0.88 μg/g. The results indicated that compound I was rapidly distributed and could cross the blood-brain barrier. The pharmacokinetic profile summarized provides valuable information for the further investigation of compound I as a potential anti-glioblastoma agent.

Pharmacokinetics and brain distribution studies of 6-hydroxykynurenic acid and its structural modified compounds.

6-Hydroxykynurenic acid (6-HKA) is an organic acid component in extracts of Ginkgo biloba leaves and acts as a major contributor to neurorestorative effects, while its oral bioavailability was low. Therefore, using prodrug method to improve the bioavailability and brain content of 6-HKA is significant. Three structural modified compounds of 6-HKA were synthesized, and ultra performance liquid chromatography-tandem mass spectrometry methods for quantification of these structural modified compounds in rat plasma and rat brain homogenate were established and comprehensively validated. The methods were effectively applied to investigate the effects of structural modification on apparent permeability coefficients in cells, the pharmacokinetics and the brain distribution in rats. The results illustrated that esterification can greatly improve the apparent permeability coefficient and bioavailability of 6-HKA. Comparing with direct oral administration of 6-HKA, the bioavailability of isopropyl ester was greatly improved (from 3.96 ± 1.45% to 41.8 ± 15.3%), and the contents of 6-HKA in rat brains (49.7 ± 9.2 ng/g brain) were significantly higher after oral administration. The bioavailability and the brain content of 6-HKA can be improved by the prodrug method. Among three structural modified compounds, isopropyl-esterified 6-HKA was the most promising treatment.

Fabrication and Characterization of Paclitaxel and Resveratrol Loaded Soluplus Polymeric Nanoparticles for Improved BBB Penetration for Glioma Management.

Gliomas are one of the prominent cancers of the central nervous system with limited therapeutic modalities. The present investigation evaluated the synergistic effect of paclitaxel (PAX) and resveratrol (RESV)-loaded Soluplus polymeric nanoparticles (PNPs) against glioma cell lines along with in vivo pharmacokinetics and brain distribution study. PAX-RESV-loaded PNPs were prepared by the thin film hydration technique and optimized for different dependent and independent variables by using DoE (Design-Expert) software. The in vitro physiochemical characterization of prepared PAX-RESV-loaded PNPs exhibited appropriate particle size, PDI and % encapsulation efficiency. Cytotoxicity assay revealed that PTX-RESV loaded PNPs had a synergistic antitumor efficacy against C6 glioma cells compared with single and combined pure drugs. Finally, the pharmacokinetic and brain distribution studies in mice demonstrated that the PNPs significantly enhanced the bioavailability of PTX-RESV PNPs than pure PAX and RESV. Thus, the study concluded that PAX-RESV PNPs combination could significantly enhance anti-glioma activity, and this could be developed into a potential glioma treatment strategy.

Nanostructured lipid carrier to overcome stratum corneum barrier for the delivery of agomelatine in rat brain; formula optimization, characterization and brain distribution study

The current work attempted to achieve bypassed hepatic metabolism, controlled release, and boosted brain distribution of agomelatine by loading in NLC and administering via transdermal route. Agomelatine-loaded NLC (AG-NLC) was fabricated employing melt-emulsification technique and optimized using central composite design. The optimized AG-NLC had 183.16 ± 6.82 nm particle size, 0.241 ± 0.0236 polydispersity index, and 83.29 ± 2.76% entrapment efficiency. TEM and FESEM visually confirmed the size and surface morphology of AG-NLC, respectively. DSC thermogram confirmed the conversion of AG from crystalline to amorphous form, which indicates improved solubility of AG when loaded in NLC. For further stability and improved applicability, AG-NLC was converted into a hydrogel. The texture analysis of AG-NLC-Gel showed appropriate gelling property in terms of hardness (142.292 g), cohesiveness (0.955), and adhesiveness (216.55 g.sec). In comparison to AG-suspension-Gel (38.036 ± 6.058%), AG-NLC-Gel (89.440 ± 2.586%) exhibited significantly higher (P < 0.005) skin permeation profile during the 24 h study. In the CLSM study, Rhodamine-B loaded AG-NLC-Gel established skin penetration up to the depth of 45 µm, whereas AG-Suspension-Gel was restricted only to a depth of 25 µm. γ-scintigraphy in wistar rats revealed ~ 55.38% brain distribution potential of 99mTc-AG-NLC-Gel at 12 h, which was 6.31-fold higher than 99mTc-AG-Suspension-Gel. Overall, the gamma scintigraphy assisted brain distribution study suggests that NLC-Gel system may improve the brain delivery of agomelatine, when applied transdermally.

A validated UHPLC-MS/MS method for pharmacokinetic and brain distribution studies of twenty constituents in rat after oral administration of Jia-Wei-Qi-Fu-Yin

A rapid ultra-high performance liquid chromatography coupled with triple quadrupole tandem mass spectrometry (UHPLC-QqQ MS/MS) approach with high sensitivity and selectivity was developed for the quantification of twenty compounds, including 9 saponins, 8 flavonoids, 2 oligosaccharide esters and 1 phenolic acid, in rat plasma and brain, which was administrated intragastrically with Jia-Wei-Qi-Fu-Yin (JWQFY), Mass spectrometric detection was operated under multiple reaction monitoring (MRM) mode. All calibration curves possessed good linearity with correlation coefficients ( r2) higher than 0.9916 in their respective linear ranges. For intra- and inter-day precision, all the relative standard deviations (RSDs) at different levels were less than 14.68 %. Based on the UHPLC-QqQ MS/MS quantitative results, pharmacokinetic study and brain distribution of multiple components in JWQFY was then successfully performed. As a result, constituents with discrepancy structures showed diverse pharmacokinetic and distribution characteristics. For instance, ferulic acid (phenolic acid), 3, 6′-disinapoyl sucrose and tenuifoliside A (oligosaccharide esters) showed short Tmax (< 10 min), whereas the Tmax of ginsenosides Rb1, Rb2 and Rc (ppd-type terpenoid saponins) were much longer (> 4 h). Besides, ferulic acid, epimedin C, icariin, glycyrrhizin, ginsenoside Rb1 and ginsenoside Rg1 were considered as the potential effective ingredients of JWQFY because of their relatively high exposure to blood and brain. Our study would provide relevant information for discovery of pharmacodynamic ingredients, as well as further action mechanisms investigations of JWQFY.

Microemulsion as a promising carrier for nose to brain delivery: journey since last decade

Tight junctions and efflux transporters are two chief bodyguards of the blood–brain barrier that protect the brain and create challenges for the treatment of neurological disorders by hampering the systemic delivery of conventional therapeutics to the brain. Approaches involving drug delivery across the brain are either invasive which require disruption of barrier integrity, leading to develop the risk of neurological changes and brain abscess, or non-invasive patient friendly approach like intranasal delivery. Several investigations have strongly confirmed the direct connection between nose and brain via olfactory and trigeminal pathway which deliver neurotherapeutics directly to the brain bypassing obstructive barriers. Since last two decades, extensive researches are ongoing for intranasal delivery of drugs in the form of different novel colloidal carriers wherein, microemulsion with their unique composition and small globule size (< 100 nm) have shown higher efficacy in-vivo and revealed their great potential to treat severe brain disorders where rapid onset of action is needed. In this discussion, why intranasal delivery of microemulsion seems to be promising for brain targeting is the foremost focus while, the importance of delivery device for efficient brain targeting is also covered. Considering the translation of positive in-vivo outcomes further into clinical studies and humans, future direction should be aimed at evaluating the suitability of microemulsion with an efficient intranasal delivery device capable of delivering formulation into upper nasal segment. Limitations associated to intranasal delivery of microemulsion such as performing brain distribution studies in most appropriate model resembling humans, impact of diseased condition on the drug absorption and toxicity related to prolonged use, etc. must be addressed in the near future to establish a strong bench to bedside platform.

Pharmacokinetics and brain distribution studies of perphenazine-loaded solid lipid nanoparticles

Background Perphenazine (PPZ) is a typical antipsychotic that is mainly administrated for the treatment of schizophrenia. Due to its highly lipophilic nature and extensive hepatic first-pass metabolism, its oral bioavailability is low (40%). Objective The novel nanocarriers like solid lipid nanoparticles (SLN) have been reported to be highly effective for improving the therapeutic effect of drugs. Therefore the main scope of the present investigation was the evaluation of in vivo characteristics of PPZ-SLN in terms of pharmacokinetic parameters and brain distribution. Methods The PPZ-SLN was prepared by the solvent-emulsification and evaporation method. The storage stability of PPZ-SLN and empty SLN powders was studied for 3 months. In vivo pharmacokinetic studies and brain distribution evaluations were performed following a single oral dose administration of PPZ and PPZ-SLN suspensions on male Wistar rats. An HPLC method was established and validated for the quantitative determination of PPZ in plasma and brain samples. Results The storage stability studies revealed the good storage stability of the both PPZ-SLN and empty SLN at 4 °C. Compared to PPZ suspension, the relative bioavailability and the brain distribution of PPZ-SLN were increased up to 2-fold and 16-fold, respectively. Mean residence time (MRT) and half-life (t1/2) of PPZ-SLN were significantly (p value < 0.01) increased in both plasma and brain homogenate compared to PPZ suspension. Conclusion The significant improvement in the pharmacokinetic properties of PPZ following one oral dose indicates that SLN is a promising drug delivery system for PPZ and shows a high potential for successful brain delivery of this antipsychotic.